The lysosomal system has come to be appreciated as a critically important component of virtually all eukaryotic cells. It is responsible for the digestion of food materials, the turn-over of cellular material, and the secretion of lysosomal enzymes. Lysosomes are also implicated in many other functions including: the immune system, autolysis, resorption of extracellular matricies, resculpturing of cell surfaces, and modulation of drug and hormone action. The relevance of lysosomal function to human diseases is well established. Many human lysosomal genetic diseases have been identified which involve deficiencies of lysosomal enzymes or alterations in their secretion. The lysosomal system is also involved in diseases such as arthritis or inflammation where secreted lysosomal enzymes are thought to be responsible for much or most of the tissue damage. The study of lysosomal enzymes is related to the basic functioning of cells since an understanding of how these enzymes are synthesized, packaged into the vesicular system, and transported to particular vesicles would advance our understanding of basic molecular and cellular biology. We propose to investigate the synthesis of seven lysosomal enzymes including the processing and modification mechanisms leading to the final mature enzyme. We will concentrate on the similarities in enzyme modification that may act as recognition signals for intracellular localization. Radiochemical labelling will be used to characterize the type of modifications present and the modifications that are common to many lysosomal enzymes will be studied immunologically. The study of the many lysosomal enzyme secretory mutants we have isolated will permit evaluation of the role of enzyme modification in intracellular localization and the functioning of the lysosomal system. Dictyostelium discoideum will be the subject of this study because of its accessibility for both biochemical and genetic studies.